Cerebral white matter (WM) abnormalities on magnetic resonance imaging (MRI) correlate with neurodevelopmental disability in infants born prematurely.
We assessed the histopathological correlates of MRI abnormalities in a baboon model of premature birth. Baboons were delivered at 125 days gestation (dg, term ~ 185 dg) and maintained in an animal intensive care unit for 14 (n = 26) or 28 days (n = 17). Gestational control animals were delivered at 140 dg (n = 9) or 153 dg (n = 4). Cerebral WM in fixed brains was evaluated using MRI, diffusion tensor imaging (DTI), and histopathology.
Quantitative histological measures of WM and ventricular volumes correlated with qualitative MRI scores of WM volume loss and ventriculomegaly. Diffuse astrocytosis was associated with signal abnormality on T2-weighted imaging and higher apparent diffusion coefficient in WM. Loss of oligodendrocytes was associated with lower relative anisotropy characterized by higher radial diffusivity values. The relationship between histopathology and MRI abnormalities was more pronounced in animals in the 28 d model, equivalent to the term human infant.
MRI reflects microstructural and anatomical abnormalities that are characteristic of WM injury in the preterm brain, and these changes are more evident on MRI at term equivalent postmenstrual age.
histology; white matter injury; diffusion MRI; baboon; neonate
Repeated courses of antenatal steroids in women threatening preterm delivery have beneficial effects on lung maturation, but concern exists about the effects on the developing brain. We aimed to determine whether repeated courses of antenatal corticosteroids increased the risk of neuropathology compared to single courses or no treatment. Single course animals received antenatal steroids at 123dg (n=6). A second course was administered to the repeated course group at 137dg (n=7). Controls received no antenatal intervention (n=5). Baboons delivered naturally at term, after which necropsy was performed. Brains were assessed histologically for parameters of development and neuropathology. Body weights did not differ between the groups (p>0.05); neither did brain weight in relation to body weight. Density of glial fibrillary acidic protein-immunoreactive (IR) astrocytes in white matter was increased in the single (p<0.05) and repeated course (p<0.01) groups compared to controls. Density of myelin-basic protein-IR oligodendrocytes was reduced in the repeated course animals compared to both controls and single course groups (p<0.05); olig2-IR, which labels all cells in the oligodendrocyte lineage, showed no difference between groups. Repeated courses of antenatal corticosteroids have effects on myelination in the developing non-human primate brain which should be taken into account when determining a dosing regimen.
Non-human primate; myelination; brain development; repeated courses antenatal steroids
Diabetes represents a major public health and health system burden. As part of the Alberta's Caring for Diabetes (ABCD) Project, two quality-improvement interventions are being piloted in four Primary Care Networks in Alberta. Gaps between health research, policy and practice have been documented and the need to evaluate the impact of public health interventions in real-world settings to inform decision-making and clinical practice is paramount. In this article, we describe the application of the RE-AIM framework to evaluate the interventions beyond effectiveness.
Methods and analysis
Two quality-improvement interventions were implemented, based on previously proven effective models of care and are directed at improving the physical and mental health of patients with type-2 diabetes. Our goal is to adapt and apply the RE-AIM framework, using a mixed-methods approach, to understand the impact of the interventions to inform policy and clinical decision-making. We present the proposed measures, data sources and data management and analysis strategies used to evaluate the interventions by RE-AIM dimension.
Ethics and dissemination
Ethics approval for the ABCD Project has been granted from the Health Research Ethics Board (HREB #PRO00012663) at the University of Alberta. The RE-AIM framework will be used to structure our dissemination activities by dimension.
It will be presented at relevant conferences and prepared for publication in peer-reviewed journals. Various products, such as presentations, briefing reports and webinars, will be developed to inform key stakeholders of the findings. Presentation of findings by RE-AIM dimension will facilitate discussion regarding the public health impact of the two interventions within the primary care context of Alberta and lessons learned to be used in programme planning and care delivery for patients with type-2 diabetes. It will also promote the application of evaluation models to better assess the impact of community-based primary healthcare interventions through our dissemination activities.
A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fetal brain injury, abnormal brain development and in cases of chronic compromise, intrauterine growth restriction. Preterm birth can also be associated with injury to the developing brain and affect the normal trajectory of brain growth. This review will focus on the effects that episodes of perinatal hypoxia (acute, chronic, associated with inflammation or as an antecedent of preterm birth) can have on the developing brain. In animal models of these conditions we have found that relatively brief (acute) periods of fetal hypoxemia can have significant effects on the fetal brain, for example death of susceptible neuronal populations (cerebellum, hippocampus, cortex) and cerebral white matter damage. Chronic placental insufficiency which includes fetal hypoxemia, nutrient restriction and altered endocrine status can result in fetal growth restriction and long-term deficits in neural connectivity in addition to altered postnatal function, for example in the auditory and visual systems. Maternal/fetal inflammation can result in fetal brain damage, particularly but not exclusively in the white matter; injury is more pronounced when associated with fetal hypoxemia. In the baboon, in which the normal trajectory of growth is affected by preterm birth, there is a direct correlation between a higher flux in oxygen saturation and a greater extent of neuropathological damage. Currently, the only established therapy for neonatal encephalopathy in full term neonates is moderate hypothermia although this only offers some protection to moderately but not severely affected brains. There is no accepted therapy for injured preterm brains. Consequently the search for more efficacious treatments continues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of efficacious strategies for neuroprotection.
Developmental brain injury; inflammation; intrauterine growth restriction; neuroprotective agents; prenatal hypoxia; white matter damage
When depression accompanies diabetes, it complicates treatment, portends worse outcomes and increases health care costs. A collaborative care case-management model, previously tested in an urban managed care organization in the US, achieved significant reduction of depressive symptoms, improved diabetes disease control and patient-reported outcomes, and saved money. While impressive, these findings need to be replicated and extended to other healthcare settings. Our objective is to comprehensively evaluate a collaborative care model for comorbid depression and type 2 diabetes within a Canadian primary care setting.
We initiated the TeamCare model in four Primary Care Networks in Northern Alberta. The intervention involves a nurse care manager guiding patient-centered care with family physicians and consultant physician specialists to monitor progress and develop tailored care plans. Patients eligible for the intervention will be identified using the Patient Health Questionnaire-9 as a screen for depressive symptoms. Care managers will then guide patients through three phases: 1) improving depressive symptoms, 2) improving blood glucose, blood pressure and cholesterol, and 3) improving lifestyle behaviors. We will employ the RE-AIM framework for a comprehensive and mixed-methods approach to our evaluation. Effectiveness will be assessed using a controlled “on-off” trial design, whereby eligible patients would be alternately enrolled in the TeamCare intervention or usual care on a monthly basis. All patients will be assessed at baseline, 6 and 12 months. Our primary analyses will be based on changes in two outcomes: depressive symptoms, and a multivariable, scaled marginal model for the combined outcome of global disease control (i.e., A1c, systolic blood pressure, LDL cholesterol). Our planned enrolment of 168 patients will provide greater than 80% power to observe clinically important improvements in all measured outcomes. Direct costing of all intervention components and measurement of all health care utilization using linked administrative databases will be used to determine the cost-effectiveness of the intervention relative to usual care.
Our comprehensive evaluation will generate evidence to reliability, effectiveness and sustainability of this collaborative care model for patients with chronic diseases and depression.
Clintrials.gov Identifier: NCT01328639
Primary care; Collaborative; Diabetes; Depression; Controlled trial; Health services research
Estrogen receptors are present within the fetal brain suggesting that estrogens may exert an influence on cerebral development. Loss of placentally-derived estrogen in preterm birth may impair development.
Baboons were delivered at 125 days of gestation (term~185 days), randomly allocated to receive estradiol (n=10) or placebo (n=8) and ventilated for 14 days. Brains were assessed for developmental and neuropathological parameters.
Body and brain weights were not different between groups but the brain/body weight ratio was increased (p<0.05) in estradiol-treated animals. There were no differences (p>0.05) between groups in any neuropathological measure in either the forebrain or cerebellum. There were no intraventricular hemorrhages; one estradiol animal displayed ectactic vessels in the subarachnoid space.
Brief postnatal estradiol administration to primates does not pose an increased risk of injury or impaired brain development.
Postnatal estradiol; premature delivery; brain injury; brain development; baboon
Ibuprofen is an effective pharmacological intervention for closure of a patent ductus arteriosus in preterm infants, and is an alternative to surgical ligation; however it is not certain whether ibuprofen treatment is associated with adverse effects on the brain. Therefore, this study examined neuropathological outcomes of ibuprofen therapy for a patent ductus arteriosus. Fetal baboons were delivered at 125-days of gestation (dg, term ~185dg) by caesarean section, given surfactant and ventilated for 14-days with positive pressure ventilation. Baboons were randomly allocated to receive either ibuprofen (PPV + ibuprofen, n=8) or no therapy (PPV, n=5). Animals were euthanased on day 14 and brains assessed for cerebral growth, development and neuropathology. Body and brain weights, the total volume of the brain and the surface folding index (measure of brain growth) were not different (p>0.05) between PPV + ibuprofen-treated and PPV animals. There was no difference (p>0.05) in the number of myelin basic protein-immunoreactive oligodendrocytes, glial fibrillary acid protein-immunoreactive astrocytes or Iba1-immunoreactive macrophages/microglia in the forebrain. No overt cerebellar alterations were observed in either group. Ibuprofen treatment for patent ductus arteriosus closure in the preterm baboon neonate is not associated with any increased risk of neuropathology or alterations to brain growth and development.
Exposure to early postnatal stress is known to hasten the progression of kindling epileptogenesis in adult rats. Despite the significance of this for understanding mesial temporal lobe epilepsy (MTLE) and its associated psychopathology, research findings regarding underlying mechanisms are sparse. Of several possibilities, one important candidate mechanism is early life ‘programming’ of the hypothalamic-pituitary-adrenal (HPA) axis by postnatal stress. Elevated corticosterone (CORT) in turn has consequences for neurogenesis and cell death relevant to epileptogenesis. Here we tested the hypotheses that MS would augment seizure-related corticosterone (CORT) release and enhance neuroplastic changes in the hippocampus.
Eight-week old Wistar rats, previously exposed on postnatal days 2–14 to either maternal separation stress (MS) or control brief early handling (EH), underwent rapid amygdala kindling. We measured seizure-induced serum CORT levels and post-kindling neurogenesis (using BrdU). Three weeks post-kindling, rats were euthanized for histology of the hippocampal CA3c region (pyramidal cell counts) and dentate gyrus (DG) (to count BrdU-labelled cells and measure mossy fibre sprouting). As in our previous studies, rats exposed to MS had accelerated kindling rates in adulthood. Female MS rats had heightened CORT responses during and after kindling (p<0.05), with a similar trend in males. In both sexes total CA3c pyramidal cell numbers were reduced in MS vs. EH rats post-kindling (p = 0.002). Dentate granule cell neurogenesis in female rats was significantly increased post-kindling in MS vs. EH rats.
These data demonstrate that early life stress results in enduring enhancement of HPA axis responses to limbic seizures, with increased hippocampal CA3c cell loss and augmented neurogenesis, in a sex-dependent pattern. This implicates important candidate mechanisms through which early life stress may promote vulnerability to limbic epileptogenesis in rats as well as to human MTLE and its associated psychiatric disorders.
We evaluated the impact of randomized ventilatory strategies on specific neuronal populations of the cerebral cortex of preterm baboons. In the first series, baboons (n = 5) were delivered at 125 days of gestation (dg; term = 185 days) and exposed to 14 days of positive pressure ventilation (PPV) and compared to 140 dg controls (n = 6). In the second series, baboons were delivered at 125 dg and ventilated by either (i) PPV for 1 day followed by 27 days of nasal continuous positive airway pressure (early [EnCPAP]; n = 6) or (ii) PPV for 5 days followed by 23 days of CPAP (delayed [DnCPAP]; n = 4). Gestational controls were delivered at 153 dg (n = 3). The density of immunoreactive neurons for calretinin and somatostatin was assessed in the primary and secondary visual cortices, cingulate and parietal cortices and subiculum in paraffin sections. Compared to gestational controls, PPV for 14 days resulted in a reduction in the density of calretinin+ cells in the visual cortex (areas 17 and 18) but not in the other cortical areas. No effect of PPV was observed on somatostatin+ cells. DnCPAP, but not EnCPAP, was associated with a reduction in the density of calretinin and somatostatin+ cells in the visual cortical areas but not in the other cortical areas compared to gestational controls. Taken together, these data demonstrate that ventilatory strategies involving > 5 days of PPV have a regionally selective impact on cortical neuronal subpopulations within the visual area but not in areas of association cortex in a non-human primate model of prematurity.
Cerebral palsy; Continuous positive airway pressure (CPAP); Cortex; Interneurons
High frequency oscillatory ventilation (HFOV) may improve pulmonary outcome in very preterm infants but the effects on the brain are largely unknown. We hypothesized that early prolonged HFOV compared to low volume positive pressure ventilation (LV-PPV) would not increase the risk of delayed brain growth or injury in a primate model of neonatal chronic lung disease. Baboons were delivered at 127±1 days` gestation (dg; term ~185dg), ventilated for 22–29 days with either: LV-PPV (n=6) or HFOV (n=5). Gestational controls were delivered at 153dg (n=4). Brains were assessed using quantitative histology. Body, brain and cerebellar weights were lower in both groups of prematurely delivered animals compared to controls; the brain to body weight ratio was higher in HFOV compared to LV-PPV and the surface folding index was lower in LV-PPV compared to controls. In both ventilated groups compared to controls, there was an increase in astrocytes and microglia and a decrease in oligodendrocytes (p<0.05) in the forebrain and a decrease in cerebellar granule cell proliferation (p<0.01); there was no difference between ventilated groups. LV-PPV and HFOV ventilation in prematurely delivered animals is associated with decreased brain growth and an increase in subtle neuropathologies; HFOV may minimize adverse effects on brain growth.
Premature infants now have an improved chance of survival but the impact of respiratory therapies on the brain, particularly the cerebellum, remains unclear. We examined the effects of early nasal continuous positive airway pressure (EnCPAP) ventilation and delayed (Dn) CPAP on the development of the cerebellum in prematurely delivered baboons. The baboons were delivered at 125 ± 2 days of gestation and ventilated for 28 days with either EnCPAP commencing at 24 hours (n = 5) or DnCPAP commencing at 5 days (n = 5). Gestational controls (n = 4) were delivered at 153 days. Cerebella were assessed histologically and an ontogeny study (90 days to term) was performed to establish values for key cerebellar developmental indicators. Cerebellar weight was reduced in DnCPAP but not EnCPAP animals vs. controls; cerebellar/total brain weight ratio was increased in EnCPAP (p < 0.05) vs. control and DnCPAP animals. There was no overt damage in the cerebella of any animals, but a microstructural alteration index based on morphologic developmental parameters and microglial immunoreactivity was increased in both prematurely delivered cohorts vs. controls (p < 0.001) and was higher in DnCPAP than EnCPAP animals (p < 0.05). These results indicate that respiratory regimens can influence cerebellar development and that early compared to delayed extubation to nCPAP appears to be beneficial.
Cerebellar ontogeny; Nasal continuous positive airway pressure; Neuropathology; Nonhuman primate; Prematurity
A patent ductus arteriosus (PDA) alters pulmonary mechanics and regional blood flow in the preterm infant. Its significance with respect to brain injury and brain development are unclear. We evaluated the effects of surgical ductal ligation on the preterm baboon brain. Baboons were delivered at 125 days of gestation (dg, term ~185dg) and ventilated for 14 days (n=12). The PDA was ligated 6 days after delivery (n=7) or left untreated (n=5). Animals were euthanized at 139dg and brains compared histologically with gestational control fetuses (n=7) at 140dg. Brain and body weights were reduced (p<0.05) in both groups of ventilated preterm animals, however, the brain to body weight ratio was increased (p<0.01) in ligated but not unligated newborns compared to gestational controls. No overt lesions were observed in either premature newborn group. Astrocyte density in the neocortex and hippocampus were greatest in the unligated newborns (p<0.01). Myelination and oligodendrocytes were reduced (p<0.05) in both premature newborn groups. The brain growth and development index was reduced and the damage index was increased in prematurely delivered baboons. Surgical ligation of the PDA does not increase the incidence of brain injury and may be beneficial if the PDA is contributing to persistent pulmonary and hemodynamic instability.
non-human primate; prematurity; cerebral injury; positive pressure ventilation; brain development
The H-reflex elicited in triceps surae by percutaneous stimulation of the posterior tibial nerve was conditioned by stimuli applied through the same electrode. The differential sensitivity of motor and sensory fibres to duration of the stimulus pulse made it possible to condition the H-reflex with either a motor or a sensory stimulus. With both types of conditioning, the H-reflex was inhibited at conditioning-test intervals of 2-3 msec and was then facilitated, the peak of facilitation occurring at 5-8 msec with motor conditioning and 6-10 msec with sensory conditioning. The phase of facilitation was followed by further inhibition. We have concluded (1) that the effects of motor conditioning on the H-reflex result from the discharge of Renshaw cells activated by the antidromic volley in the motor axons, and (2) that the effects of sensory conditioning (at the times used in these experiments) are largely due to the activation of Renshaw cells secondary to the discharge of alpha motoneurones by the conditioning volley.
The human ulnar nerve has been stimulated with square-wave pulses of various fixed durations. Measurements were made of the growth of hand myograms compared with elbow neurograms and of hand myograms compared with finger neurograms, for fixed durations of pulses and increasing strength. The effect of blocking sensory action potentials with stimuli of various durations has been investigated, as well as the blocking of action potentials in motor nerve fibres by voluntary activity. It is concluded that pulses of long duration (1 msec or more) selectively stimulate sensory fibres at threshold, whereas short duration pulses (less than 200 μsec) selectively stimulate motor fibres.